2-Methyl-3-substituted-4-aryl isoquinolines

ABSTRACT

2-Methyl-3-substituted-4-aryl isoquinolines, e.g. 2-methyl-3tertiary butyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline, prepared from corresponding 2-des-methyl isoquinoline intermediates, are useful as hypolipidemic agents.

United States Patent [191 Houlihan et al.

[ 1 2-METHYL-3-SUBSTlTUTED-4-ARYL ISOQUINOLINES [75] Inventors: WilliamJ. Houlihan, Mountain Lakes; Jeffrey Nadelson, Lake Parsippany, both ofNJ.

[73] Assignee: Sandoz-Wander, lnc., Hanover, NJ.

[22] Filed: Nov. 2, 1973 [2]] App]. No.: 412,132

[52] U.S. CL... 260/283 R, 260/283 SY, 260/286 R, 260/289 R, 260/343.3,260/515 R, 260/52] R, 260/558 R, 260/559 R, 424/258 [51] Int. Cl C07d33/34 [58] Field of Search 260/283 R, 289 R [56] References Cited UNITEDSTATES PATENTS 3,666,763 5/1972 Gelhe et a] 260/289 R l lMar. 11,1975

OTHER PUBLICATIONS Gardent et al.; Chem. Abstracts, Vol. 64, 1966; p.19555a.

Helsley 260/289 R Diana 260/289 R Primary Examiner-Donald G. DausAssistant ExaminerMary C. Vaughn Attorney, Agent, or Firm-Gerald O.Sharkin; Robert C. Honor 5 Claims, N0 Drawings 12-METHYL-3-SUBSTITUTED-4-ARYL ISOQUINOLINES This invention pertains to2-methyl-3-substituted-4- aryl isoquinolines. More particularly, itconcerns 2- methyl-3-substituted-4-phenyl-1,2,3,4-tetrahydroisoquinolines, acid addition salts thereof, and processes fortheir preparation.

The tetrahydroisoquinolines of this invention may be represented by thefollowing strucutral formula:

R and R are each independently methyl or ethyl, or

R and R together represent (CH n represents 4, 5, or 6, and R and R eachindependently represent hydrogen, halo of atomic weight 19-36,trifluoromethyl, lower alkyl, ie. alkyl of 1-4 carbon atoms, e.g.methyl, ethyl, propyl, isopropyl, butyl, and the like, and lower alkoxy,ie. alkoxy having 1-4 carbon atoms, such as methoxy, ethoxy, isopropoxy,and the like, provided that R, and R may not represent alkyl at the8position, and provided further that two trifluoromethyl groups or twotertiary butyl groups or a trifluoromethyl and a tertiary butyl groupare not on adjacent carbon atoms.

The compounds of formula (I) are preparable from compounds of theformula (II) according to the following reaction scheme:

H0001! R 1 HCHO (II) (I) where R, through R and the provisos are as setout above.

Compounds (1) are prepared by treating a corresponding compound (11)with formic acid and formaldehyde for about 12-24 hours at a temperatureof about 70-1 C., conveniently at the reflux temperature of the system.Conventional solvents may be used but are unnecessary.

The compounds of formula (11) are prepared by hydrogenation ofcorresponding isoquinoline intermediates Of formula ([11) according tothe following reaction scheme:

1; R N-H (III) (II) where R through R and the provisos are as set outabove.

Compounds (111) may be converted into compounds (11) by hydrogenatingthe former with a platinum metal catalyst, such as platinum oxide ininert solvent, such as loweralkanoic acid, e.g. acetic acid, at atemperature of from about 2060C., preferably about 25-35C., at 25-100psi until about two equivalents of hydrogen are absorbed. Neither timetemperature of reaction, pressure nor the solvent used is critical.

The compounds of formula (111) may be prepared according to thefollowing reaction scheme:

and l X represents halo of atomic weight about 3580. Compounds (111) maybe prepared from compounds (IV) by hydrogenating the latter at 25-100p.s.i. in inert alcohol solvent, e.g. lower alkanols such as etha- N-CH3 4 time, temperature, pressure nor solvent utilized is criti- 80-I C.,for about one-half to 3 hours. The reaction cal in obtaining compounds(III). time and temperature are not critical.

The novel compounds of formula (IV) may be ob- As will be appreciated bypersons skilled in the art, tained according t0 the following reactionscheme: compounds (V) and (VI) may also exist in tautomeric form and theexact form of the compounds and the amount of compound in eachtautomeric form will de- R 0 35 x pend upon such factors as pH,temperature, solvent,

etc. For simplicity, compounds (V) and (VI) will be de- R R N picted byuse of the structures shown, but it will be un- A derstood that thecorresponding tautomeric forms and R 9 1 their use and production arealso contemplated by the 1 invention.

The compounds of formula (VI) may be obtained ac- (Iv) cording to thefollowing reaction scheme from compounds VII and compounds vm ,l 3 R o05 l N 2; 3 5 mrc- CB 1. (VIII) where X, R through R and the provisosare as set out where above. R through R and the provisos are as set outabove regarding compounds (VI), and

Y represents halo of atomic weight 35-80.

Compounds (VII) and (VIII) are first reacted in inert solvent such ashydrocarbon solvents, c.g. benzene or toluene, or ethers such as ethylether or tetrahydro furan, at a temperature of from about 60 to about10C. The preferred temperature range is about to 50C. and the reactionmay be run for l-l0 hours. The resulting product is then hydrolyzed byconven- Compounds (IV) are accordingly obtained by treating a compoundof formula (V) with halogenating agent such as PCI POCI SOCI PBr PBr andSOBr and the like optionally in solvent such as aromatic hydrocarbonsolvent, e.g. benzene or toluene, for about 30-90 minutes at atemperature of about 80l C., conveniently at the reflux temperature ofthe system. Neither time, temperature nor solvent are 40 't' 1. en cational techniques to provide compounds (VI).

The compounds (V) may be prepared according to The compounds of formula(VII) may be obtained the following reaction scheme: from the compoundsof the formula n 0 P R o unfit-0H 5 v N a 0 an Rh H (VI) (v) where R,through R and respecting compounds (V) the provisos are as set outabove, and provided further R 5 0 3 that R, and R may not representalkyl at a position NH CH ortho to the carbon bonded to the amide groupon an i compounds (VI), provided further that two trifluoro- 3 methylgroups or two tertiary butyl groups or a trifluoromethyl and a tertiarybutyl group are not on adjacent carbon atoms.

Compounds (V) are thus prepared from compounds (VI) by treating thelatter with polyphosphoric acid at a temperature of about -120C.,preferably about where R, and R and the provisos are as set out abovefor compounds (VI), by treatment with a lithiating agent, particularlyan alkyl or aryl lithium compound; n-butyl lithium is especiallypreferred. This reaction may be performed in solvent and for a period oftime similar to that described above in connection with the process forobtaining compounds (VI). The temperature of the reaction is preferablyfrom about l to +1 0C. Compound (VII) is normally not isolated from thereaction mixture and may be used directly in the process for preparingcompounds (Vl) above.

The compounds (IX) are preparable from compounds of the formula OK twhere R, and R are as set out above, provided that R and R may notrepresent alkyl at a position ortho to the carbon bonded to the acidgroup, and provided further that two trifluoromethyl groups or twotertiary butyl groups or a trifluoromethyl and a tertiary butyl groupare not on adjacent carbon atoms, in a standard manner by halogenatingcompounds (X) with halogenating agents such as thionyl chloride, andaminating the resulting acid halide with tert.butylamine.

The compounds (X) are prepared according to the following reactionscheme:

R 0 RI; g o

(XIII) R5 0 R5 V 0 (xx) (x) Compounds (XI) may be prepared according tothe following reaction scheme:

IHR a R on E (XII) (n) where R represents lower alkyl, as defined above,or phenyl, and

R and R are as set out above, as are the provisos respecting compounds(XI), and provided that regarding compounds (XII) R and R do notrepresent alkyl at a position ortho to the carbon bonded to the amidogroup, and provided further that two trifluoromethyl groups or twotertiary butyl gorups or a trifluoromethyl and a tertiary butyl groupare not on adjacent carbon atoms.

According to the above process, compound (Xll) is heated in inerthydrocarbon or halogenated hydrocarbon solvent, e.g. benzene, toluene,pentane, odichlorobenzene and the like. The reaction may be carried outat a temperature of about 200C., and conveniently at the refluxtemperature of the solvent utilized.

The compounds of formula (XII) are obtainable from compounds (XIII)according to thefollowing reaction scheme:

(1) lithiation where R,,, R and R and the provisos are as set out abovefor compounds (XII).

Compounds (XII) are prepared from compounds (XIII) in inert hydrocarbonor ether solvent, e.g. benzene, toluene, ethyl ether, tetrahydrofuranand the like. The reaction is a two step reaction involvinglithialithiation of the compound (XIII) to obtain a dilithiointermediate thereof, which in turn is treated with benzaldehyde toobtain compounds XII). The lithiation is preferably performed at atemperature between about -60 and +l0C. for about 1 to 3 hourswhereas'the second step, generally performed without separation of thedilithio intermediate, is performed between l0 and +l0C. for about 1-3hours.

Unless specifically indicated otherwise, the products of each of thereactions described above may be recovered by conventional techniquessuch as crystalization, filtration, trituration, and the like.

Certain of the compounds of formulae (VIII) and (XIII) are known and maybe prepared according to methods disclosed according to the literature.The compounds of formulae (VIII) and (XIII) not specifcally disclosedmay be preparedby methods analogous to those in the literature fromknown compounds.

Compounds (I), (II) and (111) may exist in the form of their acidaddition salts. Said salts and their respective free bases may beconverted from one to the other by conventional techniques and arechemically interchangeable for purposes of the above described process.The compounds of formula (I) exist in racemic form or in the form ofoptically active isomers. The separation and recovery of the respectiveisomers may be readily accomplished employing conventional techniques,and such isomers are included within the scope of the invention.

The compounds of formula (I) are useful because they possesspharmacological activity in animals as hypolipidemic agents,particularly as hyperlipoproteinemic agents, as indicated by the fall incholesterol and/or triglyceride levels in male albino Wistar ratsweighting 110-130g. initially. The rats are maintained on drug-freelaboratory chow diet for seven days and then divided into gorups of 8 to10 animals. Each group, with the exception of the control, is then givenorally 6-25 mg/kg of body weight per diem of the compound for 3-6 days.At the end of this period, the animals are anesthetized with sodiumhexobarbital and bled from the carotid arteries. Serum or plasma samplesare collected, and 1.0 ml. samples of the serum are added to 9.0 ml.redistilled isopropanol. Two autoanalyzer cupsful of a mixture ofzeolite-copper hydroxide and Lloydds reagent [Kessler, G., and Lederer,H., 1965, Technicon Symposium, Mediad Inc., New York (345-347)] areadded, and the mixture is shaken for 1 hour. Cholesterol andtriglyceride levels are determined simultaneously on the same sample byTechnicon N-24 A (cholesterol) and N-78 (triglyceride) methodology. Themean serum cholesterol levels are than computed and thehypocholesterolemic activity is expressed as the fall in cholesterollevels as a percentage of the control level. The change in serumtriglyceride levels induced by the drug is computed as a percentage ofthe control triglyceride levels.

In particular, the compounds are indicated as being useful ashypocholesterolemic agents in the treatment of hypocholesteremia.

For such usage, the compounds of formula (I) may be combined with apharmaceutically acceptable carrier or adjuvant, and may be administeredorally in such forms as tablets, capsules, elixers, suspensions and thelike, or parenterally in the form of an injectable solution orsuspension. The dosage will vary depending upon the mode ofadministration utilized and the particular compound employed.

As indicated above, the compounds of formula (I) may be similarlyadministered in the form of their nontoxic pharmaceutically acceptableacid addition salts. Such salts possess the same order of activity asthe free base, are readily prepared by reacting the base with anappropriate acid and accordingly are included within the scope of theinvention. Representative of such salts are the mineral salts, such ashydrochloride, hydrobromide, sulfate, phosphate and the like and theorganic acid salts, such as the succinate, benzoate, acetate,p-toluenesulfonate, benzenesulfonate and the like.

As noted above, the compounds of formula (I) exist as optical isomers.In come cases, greater pharmacological activity or other beneficialattribute may be found for a particular isomer and in such instancesadministration of such isomer may be preferred.

In general, satisfactory results in alleviating lipemia may be obtainedwhen the compounds (I) are administered at a daily dosage of from about05-100 mg/kg of animal body weight, preferably orally and in divideddoses, 2 to 4 times a day or in sustained release form. For most largermammals (e.g. primates) the total daily dosage is from about 30-1000 mg.per day. Dosage forms suitable for internal use comprise from about 7.5mg. to about 500 mg. of the active compound in intimate admixture with asolid or liquid pharmaceutically acceptable carrier or diluent.

Tablets containing 50 mg. of active ingredient and 250 mg. of lactosemay be prepared by conventional techniques and are useful in treatinglipemia at a dose of one tablet 2 to 4 times a day.

EXAMPLE 1 N-turt.butyl-a-phenyl-o-toluamide To a flask equipped with astirrer, dropping funnel, condenser and gas inlet tube maintained undera nitrogen atmosphere there is added at room temperature ;67.5 g. (0.5mole) N-methyl benzamide and 1200 ml.

dry tetrahydrofuran. The reaction flask is immersed in an ice bath andcooled to an internal temperature of 5C. Stirring is initiated and 688ml. of 1.6 M. n-butyl lithium (1.1 mole) in hexane is added dropwiseover about 1 hour maintaining temperature below 8C. The resultingdilithio salt is stirred at 5C. for an additional hour and then asolution of 58.5 g. (0.55 mole) of benzaldehyde in 500 ml.tetrahydrofuran is added dropwise in about 1 hour maintaining thetemperature between -1 0 and +10C. The resulting mixture is stirred at5C. for 1 hour longer and 300 ml. of saturated ammonium chloride isadded maintaining the temperature at about 10C. The layers are separatedand the organic phase dried over anhydrous magnesium sulfate, filteredand evaporated in vacuo to give a-hydroxy-N-methyl-aphenyl-o-toluamide.

A mixture of 76.5 g. of a-hydroxy-N-methyl-a-phenyl-o-toluamide and(0.314 mole) ml. 0- dichlorobenzene is heated at reflux for 18 hours.The mixture is cooled and filtered and the resulting solid trituratedwith cold ether to give 3-phenyl phthalide.

When the above detailed procedure is carried out and in place ofN-methyl benzamide there is used a. o-chloro-N-phenyl benzamide,

b. N-methyl-p-toluamide,

c. N-methyl-m-trifluoromethyl benzamide, or

d. p-methoxy-N-methyl benzamide, there is obtained through thecorresponding intermediate a-hydroxy-aphenyl-o-toluamide,

a. 7-chloro-3-phenyl phthalide,

b. 5-methyl-3-phenyl phthalide,

c. 6-trifluoromethyl-3-phenyl phthalide, or

d. 5-methoxy-3-phenyl phthalide, respectively.

A mixture of 55.2 g. of 3-phenyl phthalide (0.263 mole), 600 ml. ethanoland 5.9 g. of 10% Pd/C is hydrogenated at room temperature and 50 psiuntil 1 equivalent of H is absorbed. The catalyst is removed byfiltration and the solvent removed in vacuo and the residue trituratedin petroleum ether to give til-phenylo-toluic acid; m.p. l01104C.

To a mixture of 49.8 g. (0.235 mole) a-phenyl-otoluic acid, 300 ml.ether and 10 ml. pyridine, add dropwise with stirring 25 ml. (0.35 mole)of thionyl chloride. The resulting mixture is stirred 21 hours at roomtemperature then filtered and the solvent removed in vacuo. Theresulting acid chloride is dis- When the procedure described in theabove two paragraphs is carried out and in place of 3-phenyl phthalidethere is used a. 7-chloro-3-phenyl phthalide,

b. 5-methyl-3-phenyl phthalide,

c. 6-trifluoromethyl-3-phenyl phthalide, or

d. 5-methoxy-3-phenyl phthalide, there is obtained through thecorresponding acid and acid halide,

a. 6-chloro-N-tert.butyl-a-phenyl-o-toluamide,

b. N-tert.butyl-4-methyl-a-phenyl-o-toluamide,

c. N-tert.butyl-a-phenyl-5-trifluoromethyl-otoluamide, or

d. 4-methoxy-N-tert.butyl-a-phenyl-o-toluamide, re-

spectively.

EXAMPLE 2 N-tert.butyl-oz-phenyl-a-pivaloyl-o-toluamide To a flaskequipped with a stirrer, dropping funnel, condenser and gas inlet tubeand maintained under a nitrogen atmosphere there is added at roomtemperature 59 g. (0.221 mole) of N-tertbutyl-a-phenyl-otoluamide in1000 ml. dry tetrahydrofuran. The flask is immersed in an ice bath andcooled to an internal temperature of 5C. Stirring is initiated and 336.5mi. (0.490 mole) of n-butyl lithium in hexane) is added dropwise inabout 1 hour maintaining the temperature below 8C. The resultingsolution is stirred 2 hours at room temperature, cooled to 5C., and 26.6g. (0.221 mole) of pivaloyl chloride in 250 ml. of dry tetrahydrofuranis added dropwise maintaining temperature below 8C. After addition, themixture is stirred 2 hours at room temperature and hydrolyzed with 150ml. of saturated ammonium chloride, the resulting solution is filteredand the layers separated. The organic layer is dried over magnesiumsulfate, filtered and evaporated in vacuo. The residue is trituratedwith ether to give N-tert.butyl-a-phenyl-a-pivaloyl-otoluamide; m.p.l57-161C.

When the above process is carried out and in place of N-tert.butyl-a-phenyl-o-toluamide there is used a.6-chloro-N-tert.butyl-a-phenyl-o-toluamide, b.N-tert.butyl-4-methyl-a-phenyl-o-toluamide, c.N-terLbutyl-a-phenyl-S-triflu0romethyl-otoluamide, or d.4-methoxy-N-tert.butyl-a-phenyl-o-toluamide,

there is obtained a.6-chloro-N-tert.butyl-a-pivaloyl-a-phenyl-otoluamide, b.N-tert.butyl-4-methyl-a-pivaloyl-oz-phenyl-otoluamide, c.N-tert.butyl-a-pivaloyl-a-phenyl-S-trifluoromethyl-o-toluamide, or d.4-methoxy-N-tert.butyl-a-pivaloyl-a-phenyl-otoluamide, respectively.When the above process is carried out and in place of pivaloyl chloridethere is used 2,2-dimethylbutanol chloride or l-methylcyclohexanecarbonylbromide, there is obtained e.a-(2,2-dimethylbutanoyl)-N-tert.butyl-a-phenylo-toluamide, or f.N-tert.butyl-a-( l-methyl cyclohexanoyl)-a-phenylo-toluamide,respectively.

EXAMPLE 3 3-tert.butyl-4-phenyl isocarbostyril in portions 79 g. (0.225mole) of N-tert.butyl-aphenyl-a-pivaloyl-o-toluamide is added to 1 130mg. of polyphosphoric acid heated to C. The mixture is stirred 1 1/2hours at 90C. and poured onto ice with stirring. The resulting solid isfiltered and washed thoroughly with water. The solid is recrystallizedfrom chloroform: ethyl ether (1:1) to give3-tert.butyl-4-phenylisocarbostyril; m.p. 284-286C.

When the above process is carried out and in place of N-tert.butyl-a-phenyl-oz-pivaloyl-o-toluamide there is used a.6-chloro-N-tert.butyl-a-pivaloyI-a-phenyl-otoluamide,

b. N-tert.butyl-4-methyl-a-pivaloyla-phenyl-otoluamide,

c. N-tert.butyl-a-pivaloyl-a-phenyl-5-trifluoromethyl-o-toluamide, or

d. 4-methoxy-N-tert.butyl-a-pivaloyl-a-phenyl-otoluamide,

e. a-(2,2-dimethylbutanoyl)-N-tert.butyl-a-phenylo-toluamide, or

f. N-tert.butyl-a-(1-methy1 cyclohexanoyU-a-phenylo-toluamide, there isobtained a. 3-tert.butyl-8-chloro-4-phenyl isocarbostyril,

b. 3-tert.butyl-6-methyl-4-phenyl isocarbostyril,

c. 3-tert.butyl-4-phenyl-7-trifluoromethyl isocarbostyril,

d. 3-tert.butyl-6-methoxy-4-phenyl isocarbostyril e.3-(2,Z-dimethylbutyl)-4-phenyl isocarbostyril, or

f. 3-l(1-methyl cyc1ohexyl)-4-pheny1 isocarbostyril,

respectively.

EXAMPLE 4 3-tert.butyl-l-ch1oro 4-phenyl isoquinoline A mixture of 11 g.(0.04 mole) of 3-tert. butyl-4- phenyl isocarbostyril and 40 ml. ofphosphorous oxychloride is refluxed for 1 hour. The excess solvent isremoved in vacuo and ice is added to the residue and stirred. Theresulting solid is filtered and washed with water and recrystallizedfrom ethanol to give 3- tert.butyl-1-chloro-4-phenyl isoquinoline; m.p.139-140C.

When the above process is carried out and in place of phosphorousoxychloride there is used phosphorous pentachloride or thionyl chloride,the identical product is again obtained.

When the above process is carried out and in place of 3-tert.butyl-4-phenyl isocarbostyril there is used a.3-tert.butyl-8-chloro-4-phenyl isocarbostyril,

b. 3-tert.butyl-6-methyl-4-phenyl isocarbostyril,

c. 3-tert.buty1-4-phenyl-7-trifluoromethyl isocarbostyril,

d. 3-tert.butyl-6-methoxy-4-phenyl isocarbostyril e.3-(2,2-dimethylhutyl)-4-phenyl isocarbostyril, or

f. 3-l(l-methyl cyclohcxyl)-4-phenyl isocarbostyril,

d. isoiso- EXAMPLE 3-tert.butyl-4-phenyl isoquinoline hydrochloride Amixture of 21.7 g. (0.073 mole) of 3-tert.butyl-lchloro-4-phenylisoquinoline, 4.09 g. (0.073 mole) potassium hydroxide, 1.09g palladiumon carbon and 1 liter of ethanol is hydrogenated at room temperature and50 psi until 1 equivalent of hydrogen is absorbed. The catalyst isfiltered off and washed with ethanol, combined ethanol portions areevaporated in vacuo. The residue is dissolved in ethyl ether, washedwith water, dried, and filtered and the filtrate treated with gaseousHCl. The resulting white solid is filtered and recrystallized fromethanolethyl ether, washed with water, dried, and filtered and thefiltrate treated with gaseous HCl. The resulting white solid is filteredand recrystallized from ethanol-ethyl ether (1:1 to give 3-tert.butyl-4-phenyl isoquinoline hydrochloride; m.p. 236238C.

When the above process is carried out and in place of 3-tert.butyl-l-chloro-4-phenyl isoquinoline there is used a.3-tert.butyl-l,8-dichloro-4-phenyl isoquinoline,

b. 3-tert.butyl-l-chloro-6-methyl-4-phenyl isoquinoline,

c. 3-tert.butyl-1-chloro-4-phenyl-7-trifluoromethyl isoquinoline,

cl. 3-tert.butyl-l-chloro-6-methoxy-4-phenyl isoquinoline,

e. 3-(2,2-dimethylbutyl)-l -chloro-4-phenyl isoquinoline, or

f. 3-( l-methylcyclohexyl)- l -chloro-4-phenyl isoquinoline,

there is obtained as the hydrochloride a. 3-tert.butyl-8-chloro-4-phenylisoquinoline,

b. 3-tert.butyl-6-methyl-4-phenyl isoquinoline,

c. 3-tert.butyl-4-phenyl-7-trifluoromethyl isoquinoline,

d. 3-tert.butyl-6-methoxy-4-phenyl isoquinoline,

e. 3-(2,2-dimethylbutyl)-4-phenyl isoquinoline, or

f. 3-(1-methylcyclohexyl)-4-phenyl isoquinoline, re-

spectively.

EXAMPLE 6 3-tert.butyl-4-phenyl-l ,2,3,4-tetrahydroisoquinoline Amixture of 28.5 g. (O.ll mole) of 3-tert. butyl-4- phenyl isoquinoline,2.85 g. platinum oxide and 300 ml. of acetic acid is hydrogenated atroom temperature and 50 psi until two equivalents of hydrogen areabsorbed. The catalyst is filtered off and the acetic acid is evaporatedin vacuo. The residue is dissolved in ether, washed with 50% sodiumhydroxide, water and saturated sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated. The residue is crystallizedfrom petroleum ether to give 3-tert.butyl-4- phenyl-l,2,3,4-tetrahydroisoquinoline; m.p. 79-8lC.

When the above process is carried out and in place of 3-tert.butyl-4-phenyl isoquinoline there is used a.3-tert.butyl-8-chloro-4-phenyl isoquinoline,

b. 3-tert.butyl-6-methyl-4-phenyl isoquinoline,

c. 3-tert.butyl-4-phenyl-7-trifluoromethyl isoquinoline,

d. 3-tert.butyl-6-methoxy-4-phenyl isoquinoline,

e. 3-(2,2-dimethylbutyl)-4-phenyl isoquinoline, or

f. 3-( l -methylcyclohexyl)-4-phenyl isoquinoline, there is obtained a.2-tert.butyl-8-chloro-4-phenyl-1,2,3 ,4-

tetrahydroisoquinoline, b. 3-tert.butyl-6-methyl-4-phenyll ,2,3,4-

tetrahydroisoquinoline, c. 3-tert.butyl-4-phenyl-7-trifluoromethyl-l,2,3 ,4-

tetrahydroisoquinoline,

3-tert.butyl-6-methoxy-4-phenyl-1,2,3 ,4- tetrahydroisoquinoline, e.3-(2,2-dimethylbutyl)-4-phenyll ,2,3,4-

tetrahydroisoquinoline, or f. 3-( l-methylcyclohexyl)-4-phenyl-l ,2,3,4-

tetrahydroisoquinoline, respectively.

EXAMPLE 7 3-tert.butyl-2-methyl-4-phenyl-1,2,3,4- tetrahydroisoquinolinehydrochloride A mixture of 4.50 g. (0.017 mole) of 3-tert.butyl-4-phenyl-l,2,3,4-tetrahydroisoquinoline, 4.5 g. of formic acid and 6.3 g.of 37% aqueous formaldehyde is refluxed i8 hours. The cooled mixture istreated with 2N hydrochloric acid and ether. The layers are separatedand the organic phase is washed with 2N hydrochloric acid. The aqueousphases are combined and made basic with 50% sodium hydroxide andextracted with chloroform. The chloroform extracts are dried andevaporated, the residue dissolved in ether and treated with gaseoushydrogen chloride to give 3-tert.butyl-2- methyl-4-phenyl-l,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 192-195C.

When the above detailed procedure is carried out and in place of3-tert.butyl-4-phenyl-l,2,3,4- tetrahydroisoquinoline, there is used a.2-tert.butyl-8-chloro-4-phenyl-l ,2,3,4-

tetrahydroisoquinoline,

3-tert.butyl-6-methyl-4-phenyl-l ,2,3,4- tetrahydroisoquinoline,

c. 3-tert.butyl-4-phenyl-7-trifluoromethyl-l ,2,3 ,4-

tetrahydroisoquinoline,

3-tert.butyl-6-methoxy-4-phenyl-l ,2,3,4- tetrahydroisoquinoline,

e. 3-( 2,2-dimethylbutyl )-4-phenyl-l ,2,3 ,4-

tetrahydroisoquinoline, or

f. 3-( 1-methylcyclohexyl)-4-phenyl-l ,2,3,4-

tetrahydroisoquinoline there is obtained as the hydrochloride a. 2-tert.butyl-8-chloro-2-methyl-4-phenyll ,2,3 ,4

tetrahydroisoquinoline,

3-tert.butyl-2,6-dimethyl-4-phenyl-1,2,3,4-

tetrahydroisoquinoline; m.p. 8889C. as free base,

c. 3-tert.butyl-2-methyl-4-phenyl-7-trifluoromethyl- 1,2,3,4-tetrahydroisoquinoline,

d. 3-tert.butyl-6-methoxy-2-methyl-4-phenyl-1,2,3,4-

tetrahydroisoquinoline; m.p. 72.573.5C. as free base,

e. 3-(2,2-dimethylbutyl)-2-methyl-4-phenyl-l,2,3,4-

tetrahydroisoquinoline, or

f. 3-( 1-methylcyclohexyl)-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline; m.p. 67-75C., respectively.

The title compound of this example is effective when orally administeredto an animal suffering from lipemia at a dosage of 200 mg. twice perday.

What is claimed is:

l. A compound of the formula where R represents where R and R are each,independently, methyl or ethyl, or R and R together represent (CH wheren represents 4, 5, or 6,

and R and R each, independently, represent hydrogen, halo of atomicweight 19-36, trifluoromethyl, lower alkyl, or lower alkoxy, providedthat R and R may not represent alkyl at the 8-position, and providedfurther that two trifluoromethyl or two tertiary butyl groups or atrifluoromethyl and a tertiary butyl group are not on adjacent carbonatoms and the pharmacologicaliy acceptable acid addition salts thereof.

2. The compound of claim 1 which is 3-tert.butyl-2- methyl-4-phenyl-l,2,3,4-tetrahydroisoquinoline.

3. The compound of claim 1 which is 3-tert.butyl-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride.

4. The compound of claim 1 which is 3-tert.butyl-2,6-dimethyl-4-phenyl-l ,2,3,4-tetrahydroisoquinoline.

5. The compound of claim 1 which is 3-tert.butyl-6-methoxy-2-methyl-4-phenyll ,2,3 ,4- tetrahydroisoquinoline.

1. A COMPOUND OF THE FORMULA
 1. A compound of the formula
 2. The compound of claim 1 which is 3-tert.butyl-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline.
 3. The compound of claim 1 which is 3-tert.butyl-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride.
 4. The compound of claim 1 which is 3-tert.butyl-2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline. 